The organization of the mammalian brain is determined in large part by precise genetic control of neuronal migration during development. Mutation in genes that regulate neuronal migration leads to disorders that range in severity from epilepsy to mental retardation. This project is focused on the molecular machinery that determines the final position of neurons. Specifically, we study the genes that encode components of a signaling cascade that includes an extracellular ligand, Reelin; two receptors, ApoER2 and VLDLR; and a cytoplasmic docking protein, Dab1. Binding of Reelin to its receptors leads to Dab1 tyrosine phosphorylation. We have identified phosphotyrosine-dependent Dab1 binding proteins, including Crk and Nckb, and are characterizing a role for them in Reelin signaling. We have recently shown that reducing Crk levels in neurons compromises some cellular responses to the Reelin signal. We have recently developed alleles of Dab1 that are useful for identifying genetic interactions and identifying postnatal requirements for Dab1. Using a hypomorphic allele of Dab1, we have been assessing genetic interactions with the amyloid precursor protein (APP) family of genes. Physical interactions between Dab1 and APP have been demonstrated previously; however, the function of this interaction during development is not known. Using a conditional allele of Dab1 we have identified a role for Dab1 after birth. The postnatal development of the cerebellum is aberrant in the absence of Dab1. Employing the hypomorphic and conditional alleles for Dab1, we will examine if Dab1 is required for adult nervous system functions, such as learning and memory, and we will examine whether genetic interactions between Dab1 and APP influence degeneration in a mouse model of Alzheimer?s disease.